Although it is well established that obesity is associated with insulin resistance and diabetes, the underlying mechanisms are unknown. Recent findings in our laboratory indicate that c-Jun amino terminal kinase (JNK) signaling pathway may play a role. This proposal addresses the tissue specific effects of JNK1 on the development of insulin resistance during diet-induced obesity. Our hypothesis is that obesity induces macrophage specific JNK, which leads to peripheral insulin resistance. To test this hypothesis, we will: (1) examine mice that receive a bone marrow transplantation from a) JNK deficient mice into wild type mice and b) wild type mice into JNK deficient mice and will be placed on a high fat diet and monitored metabolically, (2) screen for phosphorylation status of JNK substrates in macrophages by employing a JNK kinase that uses an ATP analogue, and (3) analyze the transcriptional profile of insulin resistant macrophages. A better understanding of the molecular mechanism of JNK in macrophages may elucidate obesity's strong association with insulin resistance and diseases of the metabolic syndrome.